1. Field of the Invention
The present invention relates to acetyl L-carnitine acid fumarate, hereinbelow briefly ALCFH, as a novel solid, crystalline and non-hygroscopic substance, a process for preparing same and the compositions comprising said substance as active principle.
In order to precisely understand the present invention, a clear distinction should be made between the formula unit 
of acetyl L-carnitine acid fumarate and the ionic compound or substance composed of fumarate and 2-(acetyloxy)-3-carboxy-N,N,N-trimethyl-1-propanaminium ions. As known, different spatial arrangements of the same constituent anions and cations may give rise to ionic substances showing totally distinct sets of physico-chemical characteristics, even though these substances are represented by the same formula unit. Such substances may, therefore, differ in the properties typical of the solid-crystalline state, such as e.g. melting point, specific melting heat, crystalline system, etc. as well as in those properties particularly relevant to their industrial applicability, such as flowability (when they occur as powder or granules), non-hygroscopicity, shelf-life and the like.
By xe2x80x9csolid crystalline substancexe2x80x9d is meant herein the ALCFH of the present invention, i.e. the substance in the form of a crystalline solid (these terms having the current meaning they take on in the technical-scientific terminology), having melting point of 105-110xc2x0 C.
By xe2x80x9cnon-hygroscopic substancexe2x80x9d is meant herein a substance showing the ability possessed by the ALCFH of the present invention, to withstand a relative humidity of a least 60%, at 25xc2x0 C., for 24 hours, when it occurs as powder or granules, without giving rise to adverse phenomena of clotting, agglomeration or even deliquescence which result in loss of their flowability.
By xe2x80x9chygroscopicxe2x80x9d is meant herein the bothersome property shown by most of L-carnitine and alkanoyl L-carnitine salts (particularly by their xe2x80x9cinner saltsxe2x80x9d) to undergo, when they occur as powders or granules, significant alteration of their flowability due to their clotting, agglomeration or even deliquescence, following exposure to an environment of relative humidity lower than 50-60%, at 25xc2x0 C., for 24 hours.
2. Description of the Prior Art
The problems of storage and processing brought about by the high hygroscopicity of L-carnitine and alkanoyl L-carnitine inner salts (among which acetyl L-carnitine inner salt) have long since been known. This high hygroscopicity renders the manufacture and storage of orally administrable solid presentation forms particularly troublesome.
However, administration forms such as tablets and capsules represent the preferred presentation forms in as much as they make it particularly easy for users to take the active ingredient and comply with optimal dosage regimens.
The problem of L-carnitine and alkanoyl L-carnitine inner salts hygroscopicity has been solved by converting these inner salts into salts of pharmacologically acceptable acids, based on the assumption that such salts maintain the same therapeutical/nutritional activities of the inner salts and do not exhibit unwanted toxic or side effects.
The finding of those pharmacologically acceptable acids which possess the ability to convert the aforesaid carnitines into stable and non-hygroscopic salts is carried out on a purely empirical basis, since no theoretical assumptions are known for selection thereof.
Although there is now an extensive body of literature, particularly patents, disclosing the production of allegedly stable, non-hygroscopic carnitine salts, actually only L-carnitine acid fumarate (U.S. Pat. No. 4,602,039 Sigma-Tau), L-carnitine L-(+)-tartrate (U.S. Pat. No. 5,703,376 Lonza) and, more recently, acetyl L-carnitine galactarate (U.S. Pat. No. 5,952,379 Sigma-Tau) have been developed on an industrial scale and marketed to date.
U.S. Pat. No. 4,602,039 (which is incorporated herein by reference) discloses a class of non-hygroscopic salts of L-carnitine and acetyl, propionyl and butyryl L-carnitine wherein the anion moieties are the anions of pharmacologically acceptable acids, among which fumarate is cited.
Fumarate anion shows remarkable advantages over the anions of other pharmacologically acceptable acids insofar as it is an intermediate in the Krebs"" cycle and is, therefore, a natural substance physiologically present in the human body, as L-carnitine and acetyl L-carnitine are.
Fumarate""s ability in assisting the metabolism of ischaemic myocardium by enhancing ATP""s production as well as its efficacy in free radicals scavenging have been demonstrated.
The aforesaid patent discloses, inter alia, L-carnitine acid fumarate and its preparation (see Example 8). As previously indicated, L-carnitine acid fumarate shows excellent shelf-life, it is non-hygroscopic and consequently has long since been on the market.
U.S. Pat. No. 4,602,039 purports also to xe2x80x9cdisclosexe2x80x9d the preparation of acetyl L-carnitine acid fumarate (see Example 6) which would be obtained as a non-hygroscopic solid having melting point of 159-161xc2x0 C.
Actually, neither repeatedly and accurately reproducing the preparation procedures disclosed in the aforesaid Example 6 nor applying to acetyl L-carnitine acid fumarate preparation the process taught in general terms in column 2, lines 18-19 of the patent, nor modifying the operational conditions and solvent selection as disclosed therein and interpreted in the light of the current skill of an average expert in organic synthesis has it ever been possible to arrive at the aforesaid compound in the form of a solid, crystalline and non-hygroscopic substance.
On the contrary, the reaction product thus obtained presents itself as a thick gluish fluid or as a layer of glassy consistency which strongly adheres to the reaction vessel walls from which it is hardly possible to remove it. The substance thus obtained does not solidify nor it is possible to determine its melting point.
In conclusion, this substance is not an industrially usable product for any purpose, particularly for anyone of the practical purposes (prolonged shelf-life in non-dehumidified environments, lasting flowability when it occurs as powder or granules, etc.) the achievement of which justifies the conversion of the various carnitine inner salts into pharmacologically acceptable salts.
It is, therefore, the object of the present invention to provide ALCFH as a solid, crystalline and non-hygroscopic substance and a process for preparing it.
Since the teachings of U.S. Pat. No. 4,602,039 do not allow such a substance to be obtained, the solid, crystalline, non-hygroscopic substance having melting point of 105-110xc2x0 C. of the present invention is, clearly, a novel substance.
The process of the present invention comprises the following steps:
(a) preparing a crystallization seed consisting essentially of acetyl L-carnitine acid fumarate by
(a.1) adding equimolar amounts of acetyl L-carnitine inner salt and fumaric acid to a lower alkanol, heating and stirring the resulting reaction mixture till complete dissolution of the reagents, thus obtaining a solution;
(a.2) cooling the solution to room temperature and adding thereto a precipitating agent in the minimum amount needed to obtain the formation of a precipitate of acetyl L-carnitine acid fumarate;
(a.3) filtering off and drying the precipitate to be used as crystallization seed in step (c);
(b) preparing a solution of equimolar amounts of acetyl L-carnitine inner salt and fumaric acid in a lower alkanol, heating and stirring the resulting reaction mixture till complete dissolution of the reagents and then cooling the solution to room temperature;
(c) seeding the solution of step (b) with the minimum amount of the crystallization seed of step (a) needed to obtain a precipitate;
(d) isolating the precipitate of step (c) by filtering it off, and drying it in an oven under vacuum thus obtaining a solid, crystalline, non-hygroscopic substance having melting point of 105-110xc2x0 C. comprised of acetyl L-carnitine acid fumarate.
It shall be apparent that step (a) of the process (i.e. the preparation of the crystallization seed consisting essentially of acetyl L-carnitine acid fumarate) is required when no ALCFH is available at all. However, whenxe2x80x94following completion of step (d)xe2x80x94large amounts of ALCFH are produced, a minute sample of this very end product may advantageously be used as crystallization seed in step (c) of the process. Consequently, step (a) may be regarded as a method of preparing a first crystallization seed to be used in a process for manufacturing considerable amounts of ALCFH. Once a first batch of ALCFH is thus produced, small portions thereof may be used as cristallization seed in any subsequent production operation.
The lower alkanol of step (a.1) and (b) is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol and the aqueous solutions thereof. Absolute ethanol and 95%-96% v/v ethanol are the preferred alkanols.
The precipitating agent of step (a.2) is selected from the group consisting of L-carnitine acid fumarate, the chlorides, carbonates and sulphates of alkali metals and alkaline-earth metals, silica and alumina. L-carnitine acid fumarate is the preferred precipitating agent.
The alkali metals and alkaline-earth metals are selected from the group consisting of sodium, potassium, magnesium and calcium. The minimum amount of the precipitating agent of step (a.2) and crystallization seed of step (c) is about 0.01-0.5% by weight to the amount of acetyl L-carnitine inner salt and fumaric acid.
In step (c) in order to increase the yield of the precipitated salt, the temperature of the seeded solution can be lowered to below room temperature, preferably to about 0xc2x0 C.-10xc2x0 C.
The following non-limiting examples show the preparation of the substance of the invention.